2. Fragile X - the commonest form of autism of known cause.
3. Myotonic dystrophy - #autosomalDominant

#2019BSQ-OCT/Q50

There are two types of HIV virus. HIV-1 is more virulent and causes most of the HIV infections, compared to HIV-2.Source-Wiki

📑Typhoid

[!INFO] Introduction to salmonella
Salmonellae are motile gram-negative bacilli that infect or colonize a wide range of mammalian hosts.
Salmonellae cause a number of clinical infections in humans; these include:

• Gastroenteritis
• Enteric fever (systemic illness with fever and abdominal symptoms)
• Bacteremia and endovascular infection
• Focal metastatic infections such as osteomyelitis or abscess
• An asymptomatic chronic carrier state
  Salmonella serotypes other than Salmonella typhi and Salmonella paratyphi are collectively known as nontyphoidal salmonellae

📑Enteric fever
📑Causative agent: Salmonella typhi AND S. Paratyphi A B and S
📑Humans are the only host of these.😔
📑Epithelium -> Peyer's patches (causing HYPERTROPHY of Peyer's patches) -> RET via lymph and blood -> Eventually, organisms reside within tissue macrophages in the liver, spleen, and bone marrow.

1. Acute illness
   Symptoms: "stepwise" fever + chills + abdominal pain 📑5-21 days after exposure. (Not rapid like cholera )
   Rose spots are non tender, blanching papules. - occurs in 2nd week.
   Intestinal rupture (3rd week) -> ? sepsis

Investigations:

• Include anemia, leukopenia, leukocytosis, and abnormal liver function tests

Diagnosis: Culture of organism from blood, stool, bone marrow, urine or rose spots / ELISA

• Widal test: Detects antibodies but can be positive in endemic areas because of past infection.

Treatment: Antibiotics :

• Fluoroquinolones [[Antibiotics#Ciprofloxacin|Cipfofloxacin]] -> ? resistant -> Ceftriaxone / cefotaxine -> ? resistant -> Meropenem;

Prevention: two types of 📑vaccinations are given : live attenuated (oral) and antigen based (IM)

• To be given to people in high risk areas (jaffna, mullativu, puttalam, nuwara eliya) and high risk occupations (food handler, HCW in contact with tyhpoid patients etc.)

Nontyphoidal salmonella

#2019BSQ-OCT/33
(search Non-typhoidal salmonella)

• They cause outbreaks of foodborne gastroenteritis
• Most commonly associated with poultry and eggs.
  • Infancts, and those aged > 60 are at higher risk of severe disease.
• Clinical features of nontyhpoidal salmonella gastroenteritis
  • Salmonella gastroenteritis is more severe than usual GE.
  • onset - 8 to 72 hours.
  • Diarrhoea, nausea, vomiting, fever and abdominal cramping.
  • However, usually self limited.
  • Fever resolves in 2-3 days but dirrhoea takes 4 to 10 days.
  • Clinically difficult to differentiate from other types of diarhoea.
  • Diagnosis requires stool culture.
  • Treatment: Antibiotics are usually not required, unless the patient is an infant or old or immunocompromised or has severe disease for some reasons.
    • When indicated, use fluorquinolone for 1 to 2 weeks.
  • Extraintestinal infection
    • Intestinal infection can progress to infect any site. Urinary infection is the commonest. (i.e long bones, visceral etc)
    • Meningitis is rare but occurs in children < 1 year old.
    • Endovascular infection is a serious complication!
      • Commonest site is infrarenal aorta.
    • Treat with ciprofloxacin, levofloxacin or ceftriaxone for 14 days.

#2019BSQ-OCT/Q32

• Methycillin resistance is caused by the PBP-2a protein, encoded by the mecA gene. PBP-2a is a cell wall synthesizing enzyme that has low affinity for beta lactam antibiotics.
  • Therefore, MRSA resists nearly all beta lactam antibiotics. Source
• Horizontal transfer causes propagation of the mecA gene.
• Methicillin resistance is defined as oxacillin minimum inhibitory concentration (MIC) ≥4 mcg/mL;
• The mec gene was probably acquired from coagulase negative staphylococci.

Community associated MRSA (CA-MRSA) infection is a known entity in which patients develop MRSA infection with no contact with healthcare settings. Presents as soft tissue infections in young, healthy people.
Risk factors for CA-MRSA

• Soft tissue injury, cosmetic body shaving, tattoos, IV drug use, incarceration, HIV infection.

Empiric coverage for MRSA is generally warranted for treatment of skin and soft tissue infections, given the high community prevalence of MRSA - UpToDate

Risk factors for infection due to HA-MRSA (Hospital acquired)

• include antibiotic use, prolonged hospitalization, intensive care, invasive devices, hemodialysis, MRSA colonization, and proximity to others with MRSA colonization or infection.

MRSA transmission:

• Occurs via contact with colonized individual or via fomites.
• Colonized individuals serve as a reservoir for transmission and also inhalation of aerosol droplets from a nasal carrier.

Treatment of MRSA infections

• Mild infections: TMP-SMX, tetracyclines or clindamycin. Fluoroquinolones should NOT be used as resistance may develop during treatment.
• For severe or rapidly progressing infection, IV vancomycin and daptomycin.

#2019BSQ-OCT/Q58

[!WARNING] Table cropped in readable length mode!!!
| #x-linked-recessive | #x-linked-recessive | #autosomalDominant ; fascioscapulohumeral is one of the commonest | #autosomalDominant , MD is the most common dystrophy among europeans | #autosomal-Recessive |
| Dystrophin present but low levels | Dystrophin absent | - | Type 1 - trinucleotide repeat, Type 2 - tetranucleotide repeat | Degeneration of cranial nerve nuclei in brain stem and anterior horn cells in the spinal cord. (I.e affects the lower motor neurons) |
| Remain ambulatory beyond 16 yo; | Death by 20 years; apparent by age 4. | Onset 10 – 40 years but normal life expectancy due to slow progression | Onset of symptoms: 20 – 50 years | From infancy to adulthood depending on severity of phenotype |
| Survive to over 30 yo; | Gower’s sign, Calf pseudohypertrophy Proximal limb weakness | Face, Shoulders, Scapular winging, Foot drop Typically asymmetrical | Distal muscle weakness, Ptosis, weakness of facial muscles and sternocleidomastoid | Diffuse, symmetrical proximal weakness, Lower limb > Upper limb Absent tendon reflexes |
| - | Myocardium is affected -> Can cause Dilated C. myopathy | May have deafness and retinal involvement. | Many systems affected: Endocrine → Small pituitary fossa and hypogonadism Frontal baldness Impaired glucose tolerance Cataracts Cardiomyopathy with conduction defects Oesophageal dysfunction | - |

• Dysphagia + dysarthria + and ipsilateral loss of taste and loss of ipilateral gag reflex - involvement of nucleus ambiguus and nucleus tractus solitarius.
  • NA - common nucleus for efferents of CN IX and X
  • NTS - has two parts (see image below)
    • Caudal - visceral afferents for cardiorespiratory control.(barroreceptors and chemoreceptors in the carotid body via CN IX and from the aortic arch via CN X)
    • Rostral = gustatory nuc. = taste afferents via CN VII (ant. 2/3 of tongue), CN IX (post. 1/3) and X (taste from epiglottis) Source
  • Nystagmus -> maybe due to vestibular nucleus involvement.
    
    #2019BSQ-OCT/Q55

Cerebellar anatomy

Cerebellar peduncles

A wide variety of manifestations are possible. These can be remembered using the acronym ‘DANISH‘:

• Dysdiadochokinesia (difficulty in carrying out rapid, alternating movements)
• Ataxia
• Nystagmus (coarse)
• Intention tremor
• Scanning speech
• Hypotonia

[!INFO] Cerebellar damage also causes
Decomposition of movement
Impairment of motor learning - no adaptation of vestibulooccular reflex.
Source

Functional anatomy

1. Cerebrocerebellum - consists of the lateral hemispheres -> Important in coordination of visually guided movements.
2. Spinocerebellum - Regulates body movements and receives proprioceptive information
3. Vestibulocerebellum - consists of the flocculonodular lobe; controls balance, ocular reflexes and fixation on a target and maintenance of posture.
   

Thus, the inputs to the cerebellum are conveyed primarily through the inferior and middle cerebellar peduncles, whereas the outputs are conveyed primarily through the superior cerebellar peduncle Source

| Epstein–Barr virus | • 40% of Hodgkin lymphoma • >95% of endemic Burkitt lymphoma • 10% gastric carcinoma • Most (type II and III) nasopharyngeal carcinoma • kaposi sarcoma • Other lymphomas (NK cell lymphomas) | • East Asia • East Africa • Regions of the Americas |

Summary of pathogenesis

#2019BSQ-OCT/Q46

HTLV is the only RNA oncovirus (which is mentioned in Robbins)

• HTLV - RNA virus - Promotes T cell replication via induction of T cell cytokines and T cell cytokine receptors via the viral TAX protein. Show tropism for CD4+ cells, just like HIV. (also an RNA virus)
  • 

Oncogenic DNA viruses

• HPV, EBV, KSHV/HHV8, Hep B (❗i.e Hep C isn't in this high risk group❗) virus are strongly associated with cancer.
• HPV
  • 1,2,4,7 - cause benign warts. (mnemonic: 2714*97)
  • 6 and 11 are low risk.
  • 18 and 18 are high risk.
  • oncogenic potential is due to production of E6 and E7 proteins. Their action 'simulates' the loss of tumor suppressor genes.
• EBV
  • First virus shown to have oncogenic potential.
  • Produces LMP1 protein which prevents apoptosis by activating BCL2.
  • Also produces EBNA2.
  • Immunocompetent hosts control EBV infection and it only results in asymptomatic infection of infectious mononucleosis.
  • In patients with deficient T cell function (HIV and organ transplant), EBV infected B cells undergo clonal proliferation.
• Hep B and Hep C
  • Cause about 75% of the worlds HCCs. [[Hepatitis and Hepatocellular carcinoma]]
  • Oncogenic effects are multifactorial. Related to chronic inflammation and DNA damage by reactive oxygen species.
    They DO NOT ENCODE ANY VIRAL ONCOPROTEINS.
  • Chronic inflammatory cells stimulate the NF-κB pathway which inhibits apoptosis so that cells with damaged DNA can survive.
  • ❗HCV is NOT a DNA VIRUS❗. <- 'enveloped positive sense single stranded RNA virus'.
  • 
  • 

#2019BSQ-OCT/Q46
H pylori is non-invasive.
- Gastric adenocarcinoma is promoted by production of CagA by H. pylori which has effects mimicking unregulated growth stimulation.
- Maltoma: H pylori stimulates H pylori reactive T cells which drive B cell proliferation; The lymphomas are of B cell origin.
- Early H pylori eradication "cure" the lymphoma.

#2019BSQ-OCT/Q54

The complement system consists of a set of plasma glycoproteins.Source.

What follows are several images of how the complement system works;
Source

Main functions of the complement proteins

Source

[!INFO]

C3a is an anaphylatoxin
C3b is an opsonin (it binds to foreign molecules) -> it tags microorganisms as foreign.

Activation of the 3 complement pathways

Classical pathway

• This is activated by activation of the C1 complex. (which consists of q,r,s subunits; therefore called C1qr2s2)
• Activation of C1 complex occurs when C1q binds IgM or IgG. Only one IgM is require but six IgG molecules are required.Source-Wiki
• Autocatalytic activation of C1r and C1s in turn cleaves C4 and C2 into larger (C4b, C2a) and smaller (C4a, C2b) fragments.
• C4bC2a assembles on pathogen surfaces and forms the C3 convertase of the classical pathway.

Alternative pathway

Basically, C3 is constantly being hydrolysed at low levels to form C3b but this is inactivated rapidly. If the C3b happens to bind to a pathogen, it become protected from inactivation and can trigger subsequent cascade activation.
The alternative pathway does not require antibodies.
It is triggered when C3b binds to bacterial polysaccharides and other endotoxins.

More details:

The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result, a more active alternative pathway C3 convertase - called C3bBb- is formed, which is further stabilized by properdin.Source
#2019BSQ-OCT/43

#2019BSQ-OCT/Q14

#2019BSQ-OCT/29

Cohort study

Advantages of cohort study

• Can establish temporality
• Can assess the risk of multiple outcomes
• Efficient if exposure is rare.
• It is NOT efficient for rare outcomes.